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00085472can151684-sup-151567_1_supp_3674563_xdx6x5.pdf (1.54 MB)

Supplementary Figures 1 through 6 from IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis

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posted on 2023-03-31, 00:11 authored by Mihir Rajurkar, Kyvan Dang, Maite G. Fernandez-Barrena, Xiangfan Liu, Martin E. Fernandez-Zapico, Brian C. Lewis, Junhao Mao

Figure S1: Immunohistochemistry staining and quantification of IKBKE and TBK1 in human PDAC tissue microarray, and normal pancreas Figure S2: qRT-PCR and western blot showing IKBKE/TBK1 levels in response to KRAS knockdown, and effect of KRAS/IKBKE/TBK1 knockdown on PDAC cell survival and proliferation Figure S3: Histological and immunohistochemical analysis of wild type and IKBKE-null mouse pancreas Figure S4: Ki67 immunohistochemistry and quantification in age matched PanIN lesions from mice Figure S5: Characterization of stable cell lines carrying inducible IKBKE/mTOR knockdown Figure S6: Immunohistochemistry showing AKT and S6K phosphorylation in xenograft mice with IKBKE/mTOR knockdown

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ARTICLE ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTOR in PDAC cells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Cancer Res; 77(2); 320–9. ©2017 AACR.

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